Neurology 2020 05 14;94(19):e2026-e2036. Epub 2020 Apr 14.
From the Memory Unit, Department of Neurology (E.V., V.M., A.L., J.F.), Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED (E.V., V.M., A.L., J.F.), Madrid, Spain; Department of Neurobiology (E.R.-V., D.F., O.A., E.W., A.N.), Care Sciences and Society, Center for Alzheimer Research, Division of Clinical Geriatrics, and Division of Neurogeriatrics (C.G.), Karolinska Institutet, Stockholm Department of Psychology (O.A.), Stockholm University; The Aging Brain Unit (O.A., A.N.) and Unit for Hereditary Dementias (C.G.), Theme Aging, Karolinska University Hospital, Stockholm; Department of Surgical Sciences, Section of Nuclear Medicine & PET (A.W.), Uppsala University, Sweden; and Department of Neuroimaging (E.W.), Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.
Objective: To study the macrostructural and microstructural MRI correlates of brain astrocytosis, measured with C-deuterium-L-deprenyl (C-DED)-PET, in familial autosomal-dominant Alzheimer disease (ADAD).
Methods: The total sample (n = 31) comprised ADAD mutation carriers (n = 10 presymptomatic, 39.2 ± 10.6 years old; n = 3 symptomatic, 55.5 ± 2.0 years old) and noncarriers (n = 18, 44.0 ± 13.7 years old) belonging to families with mutations in either the presenilin-1 or amyloid precursor protein genes. All participants underwent structural and diffusion MRI and neuropsychological assessment, and 20 participants (6 presymptomatic and 3 symptomatic mutation carriers and 11 noncarriers) also underwent C-DED-PET.
Results: Vertex-wise interaction analyses revealed a differential relationship between carriers and noncarriers in the association between C-DED binding and estimated years to onset (EYO) and between cortical mean diffusivity (MD) and EYO. These differences were due to higher C-DED binding in presymptomatic carriers, with lower binding in symptomatic carriers compared to noncarriers, and to lower cortical MD in presymptomatic carriers, with higher MD in symptomatic carriers compared to noncarriers. Using a vertex-wise local correlation approach, C-DED binding was negatively correlated with cortical MD and positively correlated with cortical thickness.
Conclusions: Our proof-of-concept study is the first to show that microstructural and macrostructural changes can reflect underlying neuroinflammatory mechanisms in early stages of Alzheimer disease (AD). The findings support a role for neuroinflammation in AD pathogenesis, with potential implications for the correct interpretation of neuroimaging biomarkers as surrogate endpoints in clinical trials.